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- PDB-6mnx: Structural basis of impaired hydrolysis in KRAS Q61H mutant -

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Basic information

Entry
Database: PDB / ID: 6mnx
TitleStructural basis of impaired hydrolysis in KRAS Q61H mutant
ComponentsGTPase KRas
KeywordsHYDROLASE / GTPASE KRAS HYDROLYSIS
Function / homology
Function and homology information


endocrine signaling / forebrain astrocyte development / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / negative regulation of epithelial cell differentiation / type I pneumocyte differentiation / positive regulation of Rac protein signal transduction / Rac protein signal transduction / skeletal muscle cell differentiation / positive regulation of glial cell proliferation ...endocrine signaling / forebrain astrocyte development / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / negative regulation of epithelial cell differentiation / type I pneumocyte differentiation / positive regulation of Rac protein signal transduction / Rac protein signal transduction / skeletal muscle cell differentiation / positive regulation of glial cell proliferation / Signaling by RAS GTPase mutants / Signaling by RAS GAP mutants / Activation of RAS in B cells / RUNX3 regulates p14-ARF / RAS signaling downstream of NF1 loss-of-function variants / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / Signalling to RAS / glial cell proliferation / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Estrogen-stimulated signaling through PRKCZ / homeostasis of number of cells within a tissue / Signaling by PDGFRA extracellular domain mutants / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / SHC-mediated cascade:FGFR3 / Signaling by FGFR4 in disease / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / Erythropoietin activates RAS / SHC-mediated cascade:FGFR4 / Signaling by FLT3 ITD and TKD mutants / SHC-mediated cascade:FGFR1 / Signaling by CSF3 (G-CSF) / FRS-mediated FGFR3 signaling / Tie2 Signaling / Signaling by FGFR3 in disease / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / FRS-mediated FGFR1 signaling / G protein activity / Signaling by FGFR2 in disease / striated muscle cell differentiation / GRB2 events in EGFR signaling / Ras activation upon Ca2+ influx through NMDA receptor / SHC1 events in EGFR signaling / p38MAPK events / Signaling by FLT3 fusion proteins / FLT3 Signaling / EGFR Transactivation by Gastrin / small monomeric GTPase / GRB2 events in ERBB2 signaling / Signaling by FGFR1 in disease / CD209 (DC-SIGN) signaling / SHC1 events in ERBB2 signaling / Downstream signal transduction / NCAM signaling for neurite out-growth / Insulin receptor signalling cascade / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / visual learning / regulation of long-term neuronal synaptic plasticity / RAF activation / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / Signaling by high-kinase activity BRAF mutants / Constitutive Signaling by EGFRvIII / MAP2K and MAPK activation / Ca2+ pathway / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / Signaling by SCF-KIT / extrinsic component of cytoplasmic side of plasma membrane / Regulation of RAS by GAPs / GDP binding / Negative regulation of MAPK pathway / regulation of protein stability / RAS processing / Signaling by RAF1 mutants / actin cytoskeleton organization / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / Signaling by moderate kinase activity BRAF mutants / Signaling by BRAF and RAF1 fusions / MAPK cascade / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / DAP12 signaling / Ras protein signal transduction / neuron apoptotic process / RAF/MAP kinase cascade / mitochondrial outer membrane / negative regulation of neuron apoptotic process / GTPase activity / positive regulation of protein phosphorylation / Golgi membrane / focal adhesion
Similarity search - Function
Small GTPase, Ras-type / small GTPase Ras family profile. / Rho (Ras homology) subfamily of Ras-like small GTPases / Small GTPase / Ras family / Small GTP-binding protein domain / P-loop containing nucleotide triphosphate hydrolases / P-loop containing nucleoside triphosphate hydrolase / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
GUANOSINE-5'-TRIPHOSPHATE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsBera, A.K. / Westover, K.D.
CitationJournal: Cancer Res. / Year: 2020
Title: KRASQ61HPreferentially Signals through MAPK in a RAF Dimer-Dependent Manner in Non-Small Cell Lung Cancer.
Authors: Zhou, Z.W. / Ambrogio, C. / Bera, A.K. / Li, Q. / Li, X.X. / Li, L. / Son, J. / Gondi, S. / Li, J. / Campbell, E. / Jin, H. / Okoro, J.J. / Xu, C.X. / Janne, P.A. / Westover, K.D.
History
DepositionOct 3, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 15, 2020Provider: repository / Type: Initial release
Revision 1.1Aug 19, 2020Group: Database references / Derived calculations / Structure summary
Category: citation / citation_author ...citation / citation_author / pdbx_struct_conn_angle / struct / struct_conn
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _struct.title / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id
Revision 1.2Aug 26, 2020Group: Structure summary / Category: struct / Item: _struct.title
Revision 1.3Sep 16, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: GTPase KRas
B: GTPase KRas
C: GTPase KRas
D: GTPase KRas
E: GTPase KRas
F: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)118,97618
Polymers115,6916
Non-polymers3,28512
Water3,189177
1
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,8293
Polymers19,2821
Non-polymers5472
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,8293
Polymers19,2821
Non-polymers5472
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,8293
Polymers19,2821
Non-polymers5472
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,8293
Polymers19,2821
Non-polymers5472
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
5
E: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,8293
Polymers19,2821
Non-polymers5472
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
6
F: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,8293
Polymers19,2821
Non-polymers5472
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)56.770, 127.666, 145.031
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab

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Components

#1: Protein
GTPase KRas / K-Ras 2 / Ki-Ras / c-K-ras / c-Ki-ras


Mass: 19281.777 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Production host: Escherichia coli (E. coli) / References: UniProt: P01116
#2: Chemical
ChemComp-GTP / GUANOSINE-5'-TRIPHOSPHATE / Guanosine triphosphate


Mass: 523.180 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C10H16N5O14P3 / Comment: GTP, energy-carrying molecule*YM
#3: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Mg
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 177 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.27 Å3/Da / Density % sol: 45.93 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.1M MMT, 24% PEG 6000 and 1% 1,2-butanediol, pH 6.5

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Data collection

DiffractionMean temperature: 293 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Mar 16, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.19→50 Å / Num. obs: 54159 / % possible obs: 99.1 % / Redundancy: 10.4 % / Biso Wilson estimate: 30.58 Å2 / CC1/2: 0.92 / Rpim(I) all: 0.032 / Net I/σ(I): 24.66
Reflection shellResolution: 2.2→2.24 Å / Redundancy: 4.5 % / Mean I/σ(I) obs: 2 / Num. unique obs: 2368 / CC1/2: 0.73 / Rpim(I) all: 0.351 / % possible all: 89.3

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Processing

Software
NameVersionClassification
PHENIX1.14rc3_3199refinement
PHENIX1.14rc3_3199refinement
PDB_EXTRACT3.22data extraction
HKL-3000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4obe
Resolution: 2.2→47.91 Å / SU ML: 0.278 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 27.0459
RfactorNum. reflection% reflection
Rfree0.2542 2569 5.1 %
Rwork0.2043 --
obs0.2069 50375 92.12 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 43.79 Å2
Refinement stepCycle: LAST / Resolution: 2.2→47.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7977 0 198 177 8352
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00858389
X-RAY DIFFRACTIONf_angle_d0.712811382
X-RAY DIFFRACTIONf_chiral_restr0.05051281
X-RAY DIFFRACTIONf_plane_restr0.00411536
X-RAY DIFFRACTIONf_dihedral_angle_d17.14175140
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.240.2891520.27471243X-RAY DIFFRACTION43.53
2.24-2.280.3637830.25681575X-RAY DIFFRACTION55.47
2.28-2.330.36341160.26682034X-RAY DIFFRACTION71.91
2.33-2.390.27971340.25252515X-RAY DIFFRACTION88.39
2.39-2.450.28971790.25292787X-RAY DIFFRACTION98.6
2.45-2.510.30011310.23962868X-RAY DIFFRACTION99.67
2.51-2.590.28951550.23262842X-RAY DIFFRACTION99.9
2.59-2.670.30391400.23582863X-RAY DIFFRACTION99.93
2.67-2.770.31711400.24362861X-RAY DIFFRACTION99.97
2.77-2.880.31771720.23782847X-RAY DIFFRACTION99.87
2.88-3.010.281200.23312898X-RAY DIFFRACTION99.7
3.01-3.170.27421530.22572882X-RAY DIFFRACTION100
3.17-3.370.26271570.21492877X-RAY DIFFRACTION100
3.37-3.620.24971800.20092858X-RAY DIFFRACTION99.87
3.62-3.990.22441660.18512904X-RAY DIFFRACTION99.97
3.99-4.570.19131460.1552921X-RAY DIFFRACTION99.93
4.57-5.750.22921800.16252959X-RAY DIFFRACTION100
5.75-47.930.21161650.18023072X-RAY DIFFRACTION99.17

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